Hypertension (HTN) affects more than 50 million Americans and is associated with significantly increased risk for stroke and atherosclerosis. The 7th Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7, 2003) reported that even a mild elevation of blood pressure (BP) above normal, even if it is below the hypertensive range, can be a risk factor for cardiovascular disease (CVD) and named it "prehypertension". Prehypertension (preHTN) has drawn considerable attention since then, and a number of large population studies have reported its high prevalence (up to 50% of the adult population) and association with increased future CVD. However, the literature largely lacks a focus on the vascular biology processes that may underlie the increased risk for CVD posed by preHTN. Furthermore, little is known on the degree to which obesity contributes to vascular inflammation and dysfunction and immune cell activation among prehypertensive individuals, despite the wealth of epidemiological evidence linking higher BMI and preHTN. Given that obesity itself is also associated with inflammation, these co-existing conditions may synergistically lead to worsening of vascular health in individuals with preHTN. The overarching aim of the study is to investigate the degree and nature of the association between the level of adiposity and vascular inflammation and dysfunction in preHTN. We propose to study 1) vascular endothelial dysfunction, 2) vascular inflammation, and 3) immune cell activation in prehypertensive individuals with varying degrees of adiposity. We will study 18 to 55 year-old prehypertensive individuals (N=200) who are not taking anti-hypertensive medications and normotensive individuals (N=100) as a control group. We will examine their adiposity (% body fat by DEXA and waist circumference). A comprehensive picture of orchestrated biological events in the vascular endothelium will be investigated by following: vascular dysfunction will be assessed by flow mediated brachial artery dilation. We will examine vascular inflammation and immune cell activation by assessing levels of: endothelin-1, soluble endothelial cell adhesion molecules (CAM), plasma inflammatory cytokines, CAM expression on immune cells, cytokine producing cells upon antigen stimulation, and neutrophil oxidative burst, not only at rest but also in response to psychological and physical stressors. A standardized exercise challenge and Trier Social Stress Test are reliable and robust stress paradigms to investigate immune and cardiovascular system responses under neuroendocrine activation. We will also follow weight, BP, and inflammation changes in a subset of subjects for 2-2.5 years to gather invaluable pilot data for a follow-up grant proposal. Investigating the degree to which adiposity contributes to vascular health in preHTN and the role of adipokines will provide the evidence that the vascular damages brought by obesity-related preHTN may well be the bridge to future CVD. Findings of this study will be a basis for a follow-up longitudinal study to implement behavioral interventions to reduce adiposity and to influence more pinpointed vascular inflammatory pathways in preHTN. PUBLIC HEALTH RELEVANCE: Prehypertension is recognized as a risk factor for cardiovascular disease (CVD), but little is known of the vascular biology of this "prelude" to hypertension. We propose to investigate the degree to which adiposity contributes to vascular inflammation that may underlie future development of hypertension and CVD in prehypertensive individuals. This study of underlying vascular pathology in obesity-related prehypertension will have a significant public health impact by providing the evidence for the need for behavioral modifications to reduce obesity for the prevention of hypertension and by providing a mechanistic understanding of the contributions of obesity to immune and vascular biology ("bench-to-community, beyond bedside").